The goal of the proposed study is to evaluate the role of genetic variability and biomarkers in two specific pathways - inflammation and folate-mediated one-carbon metabolism - in colorectal cancer etiology within a large cohort of women. Strong evidence from epidemiology and experimental studies implicates inflammation and one-carbon metabolism in colorectal cancer, and preliminary studies show that these two pathways may be interconnected. However, there are many remaining questions, particularly regarding the impact of genetic factors in these pathways in the presence of differences in nutritional status or NSAID use. To date, a comprehensive assessment of the impact of genetics and relevant biomarkers on colorectal cancer risk is lacking, and can best be achieved within a large prospective study. We propose to investigate these two interrelated pathways of demonstrated relevance to colorectal carcinogenesis within the Women's Health Initiative Observational Study, a prospective cohort of >93,000 postmenopausal women who will have been followed for an average of 10.2 years. We will evaluate whether 1) genetic variability and biomarkers relevant to one-carbon metabolism are associated with colorectal cancer risk, and whether associations differ by folic-acid fortification; 2) genetic variability and biomarkers relevant to prostaglandin synthesis and inflammation are associated with colorectal cancer risk; 3) whether genetic factors modify associations with nutrients or modify the response to NSAIDs; and 4) whether there are interconnections between the two pathways. A nested case-control study is proposed, which includes 1000 incident colorectal cancer cases and 1500 matched controls. Biomarker assays derived from blood obtained at the baseline visit include vitamin B12, holo-transcobalamin II, pyridoxalphosphate (vitamin B6), homocysteine, serum and RBC folate, and global lymphocyte DNA methylation. Biomarkers of inflammation include C-reactive protein and serum amyloid A. These will be measured at two time points, allowing us to evaluate whether a rise in these inflammatory markers is predictive of risk. Genotyping will focus both on candidate polymorphisms with strong evidence for functional impact and haplotype tagSNPs, for a comprehensive assessment of genetic variability. This interdisciplinary collaborative study will be both comprehensive and cost-effective, utilizing a high- quality data source. Results will: 1) further our understanding of the role of inflammation in colorectal carcinogenesis; 2) increase our knowledge about the mechanisms linking one-carbon metabolism to colorectal carcinogenesis, including about the influence of vitamins B6 and B12, and global DNA methylation and the impact of folic-acid fortification; and 3) provide valuable information regarding the possibility of developing targeted interventions involving one-carbon nutrients or NSAIDs among genetically defined groups. Colorectal cancer is the third most common cancer in the United States and the second most common cause of cancer death among both men and women. This study will investigate the role of diet and inflammation on women's risk of colorectal cancer. A person's nutrition, use of anti-inflammatory drugs, and inherited genetic factors can interact to determine an individual's risk of colorectal cancer. Through this research, we will learn more about how to prevent colorectal cancer and about possible public health recommendations based on genetic characteristics.